Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study

Bernd C Schwahn; Francjan J Van Spronsen; Abdel A Belaidi; Stephen Bowhay; John Christodoulou; Terry G Derks; Julia B Hennermann; Elisabeth Jameson; Kai König; Tracy L McGregor; Esperanza Font-Montgomery; José A Santamaria-Araujo; Saikat Santra; Mamta Vaidya; Anne Vierzig; Evangeline Wassmer; Ilona Weis; Flora Y Wong; Alex Veldman; Günter Schwarz

doi:10.1016/S0140-6736(15)00124-5

Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study

Lancet. 2015 Nov 14;386(10007):1955-1963. doi: 10.1016/S0140-6736(15)00124-5. Epub 2015 Sep 3.

Authors

Bernd C Schwahn¹, Francjan J Van Spronsen², Abdel A Belaidi³, Stephen Bowhay⁴, John Christodoulou⁵, Terry G Derks², Julia B Hennermann⁶, Elisabeth Jameson⁷, Kai König⁸, Tracy L McGregor⁹, Esperanza Font-Montgomery¹⁰, José A Santamaria-Araujo¹¹, Saikat Santra¹², Mamta Vaidya¹³, Anne Vierzig¹⁴, Evangeline Wassmer¹², Ilona Weis¹⁵, Flora Y Wong¹⁶, Alex Veldman¹⁷, Günter Schwarz¹⁸

Affiliations

¹ Royal Hospital for Sick Children, NHS Greater Glasgow and Clyde, Glasgow, UK; Willink Biochemical Genetics Unit, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. Electronic address: bernd.schwahn@cmft.nhs.uk.
² Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, Groningen, Netherlands.
³ Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne, CECAD Cologne, University of Cologne, Cologne, Germany; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.
⁴ Royal Hospital for Sick Children, NHS Greater Glasgow and Clyde, Glasgow, UK.
⁵ Western Sydney Genetics Program, Children's Hospital at Westmead, and Disciplines of Paediatrics & Child Health and Genetic Medicine, University of Sydney, Sydney, NSW, Australia.
⁶ Villa Metabolica, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
⁷ Willink Biochemical Genetics Unit, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
⁸ Department of Pediatrics, Mercy Hospital for Women, Melbourne, VIC, Australia.
⁹ Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN, USA.
¹⁰ Children's Hospital of Wisconsin, Milwaukee, WI, USA.
¹¹ Orphatec/Colbourne Pharmaceuticals, Niederkassel, Germany.
¹² Birmingham Children's Hospital, Birmingham, UK.
¹³ Paediatric Intensive Care, Bart's Health NHS Trust, Royal London Hospital, London, UK.
¹⁴ Paediatric Intensive Care, University Children's Hospital, University of Cologne, Cologne, Germany.
¹⁵ Children's Hospital, Gemeinschaftsklinikum Koblenz-Mayen, Kemperhof, Koblenz, Germany.
¹⁶ Monash Newborn, Monash Medical Centre, The Ritchie Centre, Hudson Institute of Medical Research, and The Department of Paediatrics, Monash University, Melbourne, VIC, Australia.
¹⁷ Orphatec/Colbourne Pharmaceuticals, Niederkassel, Germany; Monash Newborn, Monash Medical Centre, The Ritchie Centre, Hudson Institute of Medical Research, and The Department of Paediatrics, Monash University, Melbourne, VIC, Australia.
¹⁸ Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne, CECAD Cologne, University of Cologne, Cologne, Germany; Orphatec/Colbourne Pharmaceuticals, Niederkassel, Germany.

PMID: 26343839
DOI: 10.1016/S0140-6736(15)00124-5

Abstract

Background: Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor.

Methods: In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80-320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP.

Findings: Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease.

Interpretation: cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit.

Funding: German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Compassionate Use Trials
Drug Administration Schedule
Female
Humans
Infant, Newborn
Male
Metal Metabolism, Inborn Errors / diagnosis
Metal Metabolism, Inborn Errors / drug therapy*
Organophosphorus Compounds / therapeutic use*
Pterins / therapeutic use*
Treatment Outcome

Substances

Organophosphorus Compounds
Pterins
nulibry

Supplementary concepts

Molybdenum cofactor deficiency